Discovery of a Covalent Inhibitor Selectively Targeting the Autophosphorylation Site of c-Src Kinase.

Autor:	Zhang H; Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan 528437, China.; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China., Xu D; Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan 528437, China.; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.; Department of Chemistry, College of Sciences, Shanghai University, Shanghai 200444, China., Huang H; Center for Chemical Biology and Drug Discovery, State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China.; University of Chinese Academy of Sciences (UCAS), 19 Yuquan Road, Beijing 100049, China., Jiang H; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China., Hu L; Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan 528437, China., Liu L; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.; University of Chinese Academy of Sciences (UCAS), 19 Yuquan Road, Beijing 100049, China., Sun G; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.; University of Chinese Academy of Sciences (UCAS), 19 Yuquan Road, Beijing 100049, China., Gao J; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.; University of Chinese Academy of Sciences (UCAS), 19 Yuquan Road, Beijing 100049, China., Li Y; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.; University of Chinese Academy of Sciences (UCAS), 19 Yuquan Road, Beijing 100049, China.; School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China., Xia C; Division of Life Science and Medicine, University of Science and Technology of China, Hefei 230026, China., Chen S; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.; University of Chinese Academy of Sciences (UCAS), 19 Yuquan Road, Beijing 100049, China., Zhou H; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.; University of Chinese Academy of Sciences (UCAS), 19 Yuquan Road, Beijing 100049, China., Kong X; Center for Chemical Biology and Drug Discovery, State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China.; University of Chinese Academy of Sciences (UCAS), 19 Yuquan Road, Beijing 100049, China., Wang M; Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan 528437, China.; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China., Luo C; Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan 528437, China.; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.; University of Chinese Academy of Sciences (UCAS), 19 Yuquan Road, Beijing 100049, China.; School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China.
Jazyk:	angličtina
Zdroj:	ACS chemical biology [ACS Chem Biol] 2024 Apr 19; Vol. 19 (4), pp. 999-1010. Date of Electronic Publication: 2024 Mar 21.
DOI:	10.1021/acschembio.4c00048
Abstrakt:	Nonreceptor tyrosine kinase c-Src plays a crucial role in cell signaling and contributes to tumor progression. However, the development of selective c-Src inhibitors turns out to be challenging. In our previous study, we performed posttranslational modification-inspired drug design (PTMI-DD) to provide a plausible way for designing selective kinase inhibitors. In this study, after identifying a unique pocket comprising a less conserved cysteine and an autophosphorylation site in c-Src as well as a promiscuous covalent inhibitor, chemical optimization was performed to obtain ( R )-LW-Srci-8 with nearly 75-fold improved potency (IC 50 = 35.83 ± 7.21 nM). Crystallographic studies revealed the critical C-F···C═O interactions that may contribute to tight binding. The k inact and K i values validated the improved binding affinity and decreased warhead reactivity of ( R )-LW-Srci-8 for c-Src. Notably, in vitro tyrosine kinase profiling and cellular activity-based protein profiling (ABPP) cooperatively indicated a specific inhibition of c-Src by ( R )-LW-Srci-8 . Intriguingly, ( R )-LW-Srci-8 preferentially binds to inactive c-Src with unphosphorylated Y419 both in vitro and in cells, subsequently disrupting the autophosphorylation. Collectively, our study demonstrated the feasibility of developing selective kinase inhibitors by cotargeting a nucleophilic residue and a posttranslational modification site and providing a chemical probe for c-Src functional studies.
Databáze:	MEDLINE
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